Screening of ETO2-GLIS2-induced Super Enhancers identifies targetable cooperative dependencies in acute megakaryoblastic leukemia

Super Enhancers (SEs) are clusters of regulatory elements associated with cell identity and disease. However, whether these elements are induced by oncogenes and can regulate gene modules cooperating for cancer cell transformation or maintenance remains elusive. To address this question, we conducte...

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Published in:Science advances 2022-02, Vol.8 (6), p.eabg9455-eabg9455
Main Authors: Benbarche, Salima, Lopez, Cécile K, Salataj, Eralda, Aid, Zakia, Thirant, Cécile, Laiguillon, Marie-Charlotte, Lecourt, Séverine, Belloucif, Yannis, Vaganay, Camille, Antonini, Marion, Hu, Jiang, da Silva Babinet, Alexandra, Ndiaye-Lobry, Delphine, Pardieu, Bryann, Petit, Arnaud, Puissant, Alexandre, Chaumeil, Julie, Mercher, Thomas, Lobry, Camille
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Cancer
Life Sciences
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Summary:Super Enhancers (SEs) are clusters of regulatory elements associated with cell identity and disease. However, whether these elements are induced by oncogenes and can regulate gene modules cooperating for cancer cell transformation or maintenance remains elusive. To address this question, we conducted a genome-wide CRISPRi-based screening of SEs in ETO2-GLIS2 acute megakaryoblastic leukemia. This approach revealed SEs essential for leukemic cell growth and survival that are induced by ETO2-GLIS2 expression. In particular, we identified a de novo SE specific of this leukemia subtype and regulating expression of tyrosine kinase-associated receptors and . Combined expression of these two receptors was required for leukemic cell growth, and CRISPRi-mediated inhibition of this SE or treatment with tyrosine kinase inhibitors impaired progression of leukemia in vivo in patient-derived xenografts experiments. Our results show that fusion oncogenes, such as ETO2-GLIS2, can induce activation of SEs regulating essential gene modules synergizing for leukemia progression.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abg9455